378 Tight Regulation of Primary Cytotoxic Response by Innate Helper Cells and its Impairment by Persisting Viruses I. M. Rouzine*1, K. Murali-Krishna2, R. Ahmed3 1Tufts Univ, Boston, MA; 2Univ of Washington, Seattle; and 3Emory Univ, Atlanta, GA
Background: Knowing exactly how different CTL types interact with each other when responding to a viral threat, and why they fail to clear some viruses, would be very instrumental in developing vaccines and antiviral drugs. In addition to experimental studies of particular cases, this requires finding a mathematical model fitting existing data on CTL kinetics. HIV/SIV and lymphocytic choreomeningitis virus in mice (LCMV) show similarities at the systemic level of host-virus interaction, such as premature depletion of antigen-specific CD8 T-cells and tropism to same types of lymphoid cells. This implies that the general mechanism of the CTL response impairment is the same for HIV/SIV and LCMV, and that the differences between the 2 viruses and between LCMV strains are due to quantitative variation of system parameters.
Methods: We checked scores of models against published data on early primary CTL response obtained in 8 independent experiments, in which the total of 15 immunological quantities has been measured. In contrast to the existing models that explain a single virus strain each, we searched for a model agreeing with all the relevant data at once, including response to individual SIV infections and 4 strains of LCMV in 2 mouse types with widely different immunopathogenesis.
Results: The simplest model which fits these data with reasonable accuracy includes 8 different subtypes of immune cells and has 15 fitting parameters. It postulates that naive CD8 T-cells differentiate into effector and dividing cells that become "transient effector" cells which either differentiate into anergic or memory cells or die. The model specifies which of these processes depend on the antigen and postulates that most of points of CTL differentiation are controlled, in a threshold fashion, by innate helper cells that are not CD4 T-cells, but either follicular dendritic cells or macrophages. The model explains the premature depletion of CTL and delayed clearance or persistence of the virus observed for SIV and LCMV assuming these viruses can infect innate helper cells to get them killed by CTL.
Conclusion: The fact that small modifications of the model impair fitting dramatically indicates that the model reflects the actual mechanism of CTL response in animals. We predict a striking effect of interference between CTL responses against similar but antigenically distinct virus strains and other methods to verify the model further.
